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Rationale and Objectives: Addiction to psychostimulant methamphetamine (METH) remains a major public health problem in the world. Animal models that use METH self-administration incorporate many features of human drug-taking behavior and are very helpful in elucidating mechanisms underlying METH addiction. These models are also helping to decipher the neurobiological substrates of associated neuropsychiatric complications. This review summarizes our work on the influence of METH self-administration on dopamine systems, transcription and immune responses in the brain., Methods: We used the rat model of METH self-administration with extended access (15 h/day for eight consecutive days) to investigate the effects of voluntary METH intake on the markers of dopamine system integrity and changes in gene expression observed in the brain at 2 h-1 month after cessation of drug exposure., Results: Extended access to METH self-administration caused changes in the rat brain that are consistent with clinical findings reported in neuroimaging and postmortem studies of human METH addicts. In addition, gene expression studies using striatal tissues from METH self-administering rats revealed increased expression of genes involved in cAMP response element binding protein (CREB) signaling pathway and in the activation of neuroinflammatory response in the brain., Conclusion: These data show an association of METH exposure with activation of neuroplastic and neuroinflammatory cascades in the brain. The neuroplastic changes may be involved in promoting METH addiction. Neuroinflammatory processes in the striatum may underlie cognitive deficits, depression, and parkinsonism reported in METH addicts. Therapeutic approaches that include suppression of neuroinflammation may be beneficial to addicted patients.

Rationale: A number of studies have compared ecstasy users to control groups on various measures of neuropsychological function in order to determine whether ecstasy use results in lasting cognitive deficits. However, few of those studies controlled adequately for non-ecstasy illicit drug use., Objective: The aim of this study was to investigate neuropsychological function in chronic ecstasy users while controlling for polydrug use., Methods: Neuropsychological function was assessed in four groups-30 current 3,4-methylenedioxymethamphetamine (MDMA) users with a little history of illicit drug use other than ecstasy and cannabis, 30 polydrug controls, 30 drug-naïve controls and 20 ex-MDMA users-using a battery of well-validated, computerized neuropsychological tests. The battery focused on memory, executive function, impulsivity and risk-taking., Results: Few differences were apparent between the groups, and on no measure were the current MDMA users impaired significantly relative to the polydrug controls. However, within the current MDMA users, questionnaire-measured impulsivity correlated with performance on a number of tests-a relationship that was not apparent in the controls., Conclusions: These data highlight the complexity in understanding the current ecstasy literature and suggest that some individuals may be particularly vulnerable to cognitive impairment following chronic use. Although no differences were identified between the current MDMA users and the controls, trait impulsiveness was significantly correlated with impairment on a number of neuropsychological outcome measures in the MDMA users, but not in the controls. These data suggest that impulsive individuals may be those most at risk for the development of cognitive impairment following chronic ecstasy use.

Rationale: In animal studies, the common club drug 3,4-methylendioxymethamphetamine (MDMA, "Ecstasy") consistently caused a prolonged loss of presynaptic serotonergic neurons, and evidence suggests that MDMA consumption may also affect the human serotonergic system. Serotonin (5-HT) has been implicated in the regulation of impulsivity and such executive functions as decision-making cognition. In fact, MDMA users have shown elevated impulsivity in two studies, but little is known about decision making in drug-free MDMA consumers., Objective: The aim of this study was to examine the cognitive neurotoxicity of MDMA with regard to behavioral impulsivity and decision-making cognition., Methods: Nineteen male, abstinent, heavy MDMA users; 19 male, abstinent cannabis users; and 19 male, drug-naïve controls were examined with the Matching Familiar Figures Test (MFFT) as well as with a Go/No-Go Task (GNG) for impulsivity and with a Gambling Task (GT) for executive functioning., Results: MDMA users showed significantly elevated impulsivity in the MFFT Impulsivity score (I-score), but not in commission errors of the GNG, compared with controls. Cannabis users did not yield altered impulsivity compared with controls. In the GT, MDMA users performed significantly worse than cannabis consumers and controls, whereas cannabis users exhibited the same decision-making capacity as controls. In addition, the I-score as well as the decision-making performance was correlated with measures of MDMA intake. The I-score and the decision-making performance were also correlated., Conclusion: These results suggest that heavy use of MDMA may elevate behavioral impulsivity and impair decision-making cognition possibly mediated by a selective impairment of the 5-HT system.

Rationale: To determine the association between MDMA misuse and neurocognition using meta-analysis., Objective: Separate analyses were conducted based on two sets of inclusion/exclusion criteria. A relatively stringent set required that the subjects be matched on important moderator variables, whereas the other did not. The study participants' performance in the following neurocognitive domains was reviewed: attention/concentration, verbal and nonverbal learning and memory, psychomotor speed and executive systems functioning., Results: In the 11 studies meeting the relatively stringent inclusion/exclusion criteria for this review, MDMA use was associated with neurocognitive deficits in each domain. Similarly, in the 23 studies meeting the relatively lenient inclusion/exclusion criteria for this review, MDMA use was associated with neurocognitive deficits in each domain. Small to medium effect sizes were generally observed. A comparison of the effect sizes across the two sets of analyses did not reveal significant differences., Conclusions: The findings from this review reveal that MDMA use is associated with neurocognitive deficits. The implications of these findings are discussed.

Rationale: Determining whether, under what circumstances, and to what extent 3,4-methylenedioxymethamphetamine (MDMA) exposure produces chronic changes in human brain function is a critical public health issue. MDMA is a widely used recreational drug commonly sold as "Ecstasy". Because findings from the animal literature have indicated that specific dosage regimens of MDMA can produce long-lasting alterations in serotonergic function, existing studies of MDMA effects in humans have examined brain serotonin (5-HT) transporters (5-HTT) and receptors or have examined brain structures or functions potentially affected by MDMA., Objectives: The objectives of this review are to provide a background for interpreting human MDMA neuroimaging research, to examine existing neuroimaging data regarding the rationale for and limitations to human MDMA research, and to provide suggestions for improving the design and interpretation of future neuroimaging approaches., Results: Of the existing neuroimaging studies in human MDMA users, few experimental designs have been replicated across different research groups. Only investigations employing nuclear imaging methods to assay brain 5-HTT levels have been replicated across methods and research laboratories. These studies have found reduced levels of the 5-HTT in recently abstinent MDMA users with some evidence for normalization of 5-HTT levels with prolonged abstinence. However, the sensitivity of these methods is unknown., Conclusions: The current state of neuroimaging in human MDMA users does not permit conclusions regarding the long-term effects of MDMA exposure. Future study designs might benefit from improved sample homogeneity, increased length of MDMA abstinence, longitudinal study design, test-retest measures, serotonergic specificity, and multimodal approaches.

Rationale: Methamphetamine (MA) dependence accounts for substantial neuropsychiatric morbidity. Furthermore, there is evidence in the literature of psychiatric and cognitive impairment in chronic users., Objectives: This report compares the general psychiatric and cognitive functioning, including impulsive decision-making, of individuals dependent on MA and normal controls., Materials and Methods: Forty-one currently abstinent individuals in treatment for MA dependence and 41 controls participated. Controls were selected to minimize group differences in age and gender. MA users met DSM-IV criteria for MA dependence, had average daily use of 0.5 g/day (0.5-6 g/day), had been abstinent at least 2 weeks (2-24 weeks), and did not currently meet criteria for other Axis I psychiatric disorders. Psychiatric symptoms were rated on standardized scales. Cognitive function was assessed with a battery of standardized neuropsychological tests. Impulsivity was assessed using a delay discounting task, which measured preference for small, immediate, and large delayed rewards., Results: The MA group reported more psychiatric symptoms than controls, and was impaired relative to controls on the Babcock Story Recall-Delayed and the Rey Auditory Verbal Learning Test. MA-dependent subjects discounted delayed rewards more than controls, and this measure of impulsivity was correlated with memory impairment in the MA group but not in the controls., Conclusions: MA-dependent individuals are more impulsive than controls, and this may be causally related to memory deficits but was unrelated to any other measure of psychiatric or cognitive impairment or any drug use history variable.